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The Journal of Neuroscience, December 17, 2008, 28(51):13805-13814; doi:10.1523/JNEUROSCI.4218-08.2008

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Neurobiology of Disease
Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Ying Liu,¹ Mi-Jeong Yoo,¹ Alena Savonenko,¹ Wanda Stirling,¹ Donald L. Price,^1,2,3 David R. Borchelt,^1,3 Laura Mamounas,¹ W. Ernest Lyons,¹ Mary E. Blue,^2,3,4 and Michael K. Lee¹

Departments of ¹Pathology, ²Neurology, and ³Neuroscience, Johns Hopkins University, Baltimore, Maryland 21205, and ⁴Kennedy Krieger Research Institute, Baltimore, Maryland 21205

Correspondence should be addressed to Dr. Michael K. Lee, Department of Pathology/Neuropathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, 558 Ross Building, Baltimore, MD 21205. Email: mklee{at}jhmi.edu

β-Amyloid (Aβ) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of Aβ pathology, including Aβ deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the Aβ neurotoxicity indicated by in vitro studies, mouse models with significant Aβ deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that Aβ pathology is insufficient for neurodegeneration in vivo. In this study, because monoaminergic (MAergic) neurons show degenerative changes at early stages of AD, we examined whether the APPswe/PS1E9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain Aβ deposition in the APPswe/PS1E9 model is associated with progressive losses of the forebrain MAergic afferents. Significantly, axonal degeneration is associated with significant atrophy of cell bodies and eventually leads to robust loss (50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local Aβ or tau pathology at the subcortical sites and precedes the onset of anxiety-associated behavior in the mice. Our results show that a transgenic mouse model of Aβ pathology develops progressive MAergic neurodegeneration occurring in AD cases.

Key words: Aβ-peptide; axon; serotonergic; noradrenergic; neuron death; BDNF; atrophy

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Received Sept. 4, 2008; revised Oct. 7, 2008; accepted Nov. 3, 2008.

Correspondence should be addressed to Dr. Michael K. Lee, Department of Pathology/Neuropathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, 558 Ross Building, Baltimore, MD 21205. Email: mklee{at}jhmi.edu

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